High risk human papilloma virus related head and neck squamous cell carcinoma (HPVHNSCC) incidence is rapidly increasing, and will soon surpass the incidence of cervical carcinoma in the US. There are no effective ways to detect preclinical or early HPVHNSCC, screen populations at increased risk for HPVHNSCC development, or even assay for microscopic persistence of HPVHNSCC after therapy. However, epigenetic alterations have been detected in body fluids from premalignant and early stage cancers and multiplex tests have shown promise for identification of patients with oral premalignancy. Our primary hypothesis is that multiplex testing of plasma and salivary rinses based on HPVHNSCC specific epigenetic alterations combined with high risk HPV DNA presence has potential as useful test for presence of HPVHNSCC. This project will serve as a discovery and diagnostic validation biomarker development trial for HPVHNSCC detection with potential application for assessment of disease response and development of a population based screening test.